4,6-Dichloro-5-Nitrobenzofuroxan: Different Polymorphisms and DFT Investigation of Its Reactivity with Nucleophiles.

This research focuses on the X-ray structure of 4,6-dichloro-5-nitrobenzofuroxan 1 and of some of its amino derivatives (4a, 4e, 4g, and 4l) and on DFT calculations concerning the nucleophilic reactivity of 1. We have found that by changing the solvent used for crystallization, it is possible to obtain 4,6-dichloro-5-nitrobenzofuroxan (1) in different polymorphic structures. Moreover, the different torsional angles observed for the nitro group in 1 and in its amino derivatives (4a, 4e, 4g, and 4l) are strictly dependent on the steric hindrance of the substituent at C-4. DFT calculations on the course of the nucleophilic substitution confirm the role of the condensed furoxan ring in altering the aromaticity of the carbocyclic frame, while chlorine atoms strongly influence the dihedral angle and the rotational barrier of the nitro group. These results corroborate previous observations based on experimental kinetic data and give a deep picture of the reaction with amines, which proceeds via a "non-aromatic" nucleophilic substitution.

On the Nucleophilic Reactivity of 4,6-Dichloro-5-nitrobenzofuroxan with Some Aliphatic and Aromatic Amines: Selective Nucleophilic Substitution.

The reaction rates for the nucleophilic aromatic substitution of 4,6-dichloro-5-nitrobenzofuroxan 1 with eight aliphatic amines (characterized by very different basicities/nucleophilicities) and three anilines have been measured in both methanol and toluene. The obtained rates have been related to the basicity (pKaH in water and Kb in benzene) or nucleophilicity (N Mayr constants) of the tested amines. The whole of the obtained kinetic data has furnished useful information on the high nucleophilic reactivity of benzofuroxan derivatives, which has been related essentially to two factors: the high electron-drawing ability/power of the condensed furoxan ring and the low aromatic character of the benzofuroxan system.

Unexpected Substituent Effects in the Iso-Heterocyclic Boulton-Katritzky Rearrangement of 3-Aroylamino-5-methyl-1,2,4-oxadiazoles: A Mechanistic Study.

The kinetics of the iso-heterocyclic mononuclear rearrangement of some 3-aroylamino-5-methyl-1,2,4-ozadiazoles was carefully examined under largely variable acidic or alkaline conditions. This reaction may proceed via two different mechanistic pathways (an uncatalyzed and a base-catalyzed one), as accounted for also by the evaluation of the relevant activation parameters. Substituent effects, as quantified by means of the Hammett's equation, appear relatively modest; however, they reveal some interesting anomalies, which enabled us to draw a very precise picture of the intimate reaction course.

Mononuclear Rearrangement of the Z-Phenylhydrazones of Some 3-Acyl-1,2,4-oxadiazoles: Effect of Substituents on the Nucleophilic Character of the >C═N-NH-C6 H5 Chain and on the Charge Density of N-2 of the 1,2,4-Oxadiazole Ring (Electrophilic Counterpart).

The reaction rates for the mononuclear rearrangement of the Z-phenylhydrazones of 3-acyl-1,2,4-oxadiazoles 3a-c into the relevant 2-phenyl-2 H-1,2,3-triazoles (4a-c) have been measured in dioxane/water at different temperatures in a large range of proton concentrations. The occurrence of two different reaction pathways (one uncatalyzed, water assisted, and the other general base catalyzed) has- been observed. The obtained results have been able to furnish information about the effects of the nature of the 3-acyl structure and of the 5-substituents in the 1,2,4-oxadiazole ring on the reactivity of the examined rearrangements: they are well in line with the previsions carried out considering some our previous computational results as well as experimental kinetic ones.

Photochemical isomerization of aryl hydrazones of 1,2,4-oxadiazole derivatives into the corresponding triazoles.

The photochemical version of the Boulton-Katritzky reaction has been studied, examining the behaviour of the arylhydrazones of 3-benzoyl-5-X-1,2,4-oxadiazoles. The effect of several modifications of the substrates structure (the E and/or Z structures of arylhydrazones, the possible presence of substituents in the arylhydrazono moiety, and the nature of substituents at C-5 of the 1,2,4-oxadiazole ring) on the course of the photochemical rearrangement has been examined.

Acid- and base-catalysis in the mononuclear rearrangement of some (Z)-arylhydrazones of 5-amino-3-benzoyl-1,2,4-oxadiazole in toluene: effect of substituents on the course of reaction.

The reaction rates for the rearrangement of eleven (Z)-arylhydrazones of 5-amino-3-benzoyl-1,2,4-oxadiazole 3a-k into the relevant (2-aryl-5-phenyl-2H-1,2,3-triazol-4-yl)ureas 4a-k in the presence of trichloroacetic acid or of piperidine have been determined in toluene at 313.1 K. The results have been related to the effect of the aryl substituent by using Hammett and/or Ingold-Yukawa-Tsuno correlations and have been compared with those previously collected in a protic polar solvent (dioxane/water) as well as with those on the analogous rearrangement of the corresponding (Z)-arylhydrazones of 3-benzoyl-5-phenyl-1,2,4-oxadiazole 1a-k in benzene. Some light can thus be shed on the general differences of chemical reactivity between protic polar (or dipolar aprotic) and apolar solvents.

Apolar versus polar solvents: a comparison of the strength of some organic acids against different bases in toluene and in water.

The constants of ion-pair formation with 3-nitroaniline (3NO(2)A) for eight halogenoacetic acids (HAAs, 3a-h: TFA, TCA, TBA, DFA, DCA, DBA, MCA, and MBA), and five 2,2-dichloroalkanoic acids containing 3-8 carbon atoms (HAs, 5a-e: DCPA, DCBA, DCMBA, DCVA, and DCOA) have been determined in TOL at 298.1 K. The results obtained brought to evidence for HAAs the formation of ion-pairs with two different stoichiometries (base-acid, 1:1 or 1:2), while in contrast the HAs furnish only the 1:1 pairs. The different steric and electronic requirements of HAAs and HAs seem to be responsible for such an unlikely behavior. At the same time, the acid-catalyzed MRH of the (Z)-phenylhydrazone of 5-amino-3-benzoyl-1,2,4-oxadiazole (1) into (2,5-diphenyl-2H-1,2,3-triazol-4-yl)urea (2) in the presence of the five HAs above has been investigated in TOL at 313.1 K. Thus, in contrast with previous results in the presence of several HAAs, a unique pathway for the rearrangement has been observed, again pointing out the importance of the above effects on the initial acid/base interactions. Finally the acidic strength of TFA against seven nitroanilines (NA, 4a-g: 4NO(2)A, 3NO(2)A, 3Me4NO(2)A, 4Me3NO(2)A, 2Me3NO(2)A, 2NO(2)A, and 3,5diNO(2)A) characterized by a very different basicity has been measured in TOL at 298.1 K.

Room temperature ionic liquids structure and its effect on the mononuclear rearrangement of heterocycles: an approach using thermodynamic parameters.

The kinetics of the rearrangement of the Z-phenylhydrazone of 3-benzoyl-5-phenyl-1,2,4-oxadiazole (1) into the relevant 4-benzoylamino-2,5-diphenyl-1,2,3-triazole (2) induced by amines have been studied in five room-temperature ionic liquids (RTILs) at different temperatures. The kinetic data collected show that both cationic and anionic parts of RTILs significantly influence the reactivity of the title reaction. The calculated activation parameters allow us to advance hypotheses about the weak interactions operating in RTIL solutions.

Study of aromatic nucleophilic substitution with amines on nitrothiophenes in room-temperature ionic liquids: are the different effects on the behavior of para-like and ortho-like isomers on going from conventional solvents to room-temperature ionic liquids related to solvation effects?

The kinetics of the nucleophilic aromatic substitution of some 2-L-5-nitrothiophenes (para-like isomers) with three different amines (pyrrolidine, piperidine, and morpholine) were studied in three room-temperature ionic liquids ([bmim][BF4], [bmim][PF6], and [bm(2)im][BF4], where bmim = 1-butyl-3-methylimidazolium and bm(2)im = 1-butyl-2,3-dimethylimidazolium). To calculate thermodynamic parameters, a useful instrument to gain information concerning reagent-solvent interactions, the reaction was carried out over the temperature range 293-313 K. The reaction occurs faster in ionic liquids than in conventional solvents (methanol, benzene), a dependence of rate constants on amine concentration similar to that observed in methanol, suggesting a parallel behavior. The above reaction also was studied with 2-bromo-3-nitrothiophene, an ortho-like derivative able to give peculiar intramolecular interactions in the transition state, which are strongly affected by the reaction medium.

On the rearrangement in dioxane/water of (Z)-arylhydrazones of 5-amino-3-benzoyl-1,2,4-oxadiazole into (2-aryl-5-phenyl-2H-1,2,3-triazol-4-yl)ureas: substituent effects on the different reaction pathways.

We have recently evidenced an interesting differential behavior in the reactivity in dioxane/water between the (Z)-2,4-dinitrophenylhydrazone (1a) and the (Z)-phenylhydrazone (1b) of 5-amino-3-benzoyl-1,2,4-oxadiazole. The former rearranges into the relevant triazole 2a only at pS+ > 4.5 while undergoing hydrolysis at high proton concentration (pS+ < 3.5); on the contrary, the latter rearranges into 2b in the whole pS+ range examined (0.1 < or = pS+ < or = 14.9). Thus, for a deeper understanding of these differences we have now collected kinetic data on the rearrangement in dioxane/water of a series of 3- or 4-substituted (Z)-phenylhydrazones (1c-l) of 5-amino-3-benzoyl-1,2,4-oxadiazole in a wide range of proton concentrations (pS+ 0.1-12.3) with the aim of gaining information about the effect of the substituent on the course of the reaction. All of the (Z)-arylhydrazones studied rearrange via three different reaction routes (specific-acid-catalyzed, uncatalyzed, and general-base-catalyzed), and the relevant results have been examined by means of free energy relationships.

Can the absence of solvation of neutral reagents by ionic liquids be responsible for the high reactivity in base-assisted intramolecular nucleophilic substitutions in these solvents?

[reaction: see text] The kinetics of the rearrangement of the Z-phenylhydrazone of 3-benzoyl-5-phenyl-1,2,4-oxadiazole (1a) into the relevant 4-benzoylamino-2,5-diphenyl-1,2,3-triazole (2a) induced by amines have been studied in two room-temperature ionic liquids (IL-1, [BMIM][BF4] and IL-2, [BMIM][PF6]). The data collected show that the reaction occurs faster in ionic liquids than in other conventional solvents previously studied (both polar or apolar, protic or aprotic). Presumably, this could depend on their peculiar ability to minimize the strong substrate-solvent, amine-solvent and amine-amine interactions occurring in conventional solvents.

On the dichotomic behavior of the Z-2,4-dinitrophenylhydrazone of 5-amino-3-benzoyl-1,2,4-oxadiazole with acids in toluene and in dioxane/water: rearrangement versus hydrolysis.

The mononuclear rearrangement (MRH) of the Z-2,4-dinitrophenylhydrazone (4a) and of the Z-phenylhydrazone (4b) of 5-amino-3-benzoyl-1,2,4-oxadiazole into the relevant triazoles 5a and 5b in toluene has been quantitatively investigated in the presence of trichloroacetic acid (TCA) and of piperidine at 313.1 K. While the behavior in the presence of piperidine recalls the one previously evidenced for some Z-hydrazones of 3-benzoyl-5-phenyl-1,2,4-oxadiazole, the study of the reactivity in the presence of TCA has most interestingly evidenced a general-acid-catalyzed rearrangement for "both" 4a and 4b. Thus, 4a offers the first example of a solvent-dependent dichotomic behavior in MRH processes on 1,2,4-oxadiazole derivatives as far as it undergoes an "acidic hydrolysis" in dioxane/water and a "rearrangement" in toluene.

The first kinetic evidence for acid catalysis in a monocyclic rearrangement of heterocycles: conversion of the Z-phenylhydrazone of 5-amino-3-benzoyl-1,2,4-oxadiazole into N,5-diphenyl-2H-1,2,3-triazol-4-ylurea.

The title reaction has been studied in dioxane/water in a large (0.1-14.9) pS+ range, evidencing, together with an uncatalyzed process at intermediate (3.5-8.0) pS+ values, the occurrence of a catalyzed pathway both in the acidic (pS+ 0.1-3.5) and in the basic region (pS+ 8.0-14.9): specific-acid catalysis and general-base catalysis, respectively, have been found to take place by means of kinetic investigations at different buffer concentrations. Mechanisms for the three pathways have been advanced on the grounds of structural features. In a comparison with previous data particular attention has been paid to the acid-catalyzed pathway, herein observed for the first time in an azole-to-azole interconversion. The mechanistic hypotheses seem well supported by ab initio calculations.

Nucleophilic Substitution Reactions of 1-Halogeno-4-COR-2-nitrobenzenes and 1-Halogeno-6-COR-2-nitrobenzenes with Sodium Benzenethiolate and Piperidine. Can an "Inverted Built-In Solvation" Be Responsible for the Peculiar Activation by an o-Carboxamido Group in S(N)Ar Reactions with an Anionic Nucleophile?

A kinetic study of the title reactions has allowed an interpretation of the higher efficiency of an o-carboxamido group with respect to an o-carbomethoxy group in activating the benzenethiolate-dehalogenation reactions in methanol (k(CONH)()2/k(CO)()2(Me) 2.2-3.0) as due to an interaction between the anionic nucleophile and the hydrogen atoms of the carboxamido group. An inversion of the activating power of the two groups (k(CONH)()2/k(CO)()2(Me) 0.14) in the reactions with the same nucleophile has been observed when they are in a para-position. Moreover, for piperidino-dehalogenation reactions in methanol k(CONH)()2/k(CO)()2(Me) ratios less than unity (0.2-0.6) have been observed independently of the position (ortho or para) of the carboxamido and carbomethoxy groups with respect to the reaction center.